The present invention provides sultam and sultone derived oxazolidinones, and more specifically, provides compounds of formula (I) described herein below. These compounds are useful as antibiotic agents.
The oxazolidinone antibacterial agents are a novel synthetic class of antimicrobials with potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, gram-negative aerobic bacteria such as H. influenzae and M. catarrhalis, as well as anaerobic organisms such as bacteroides and clostridia species, acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. 
International Publication No. WO 97/09328 discloses phenyloxazolidinones having a Cxe2x80x94C bond to 4-8 membered heterocyclic rings useful as antimicrobial agents.
U.S. Pat. No. 4,709,026 discloses ketosultams useful as sensitizers or dyes.
J. Org. Chem. 1991, 56, 3549-3556 discloses vinyl sulfonyl esters and amides in the synthesis of substituted xcex4-sultams and xcex4-sultones.
The present invention provides a compound of formula I: 
or a pharmaceutically acceptable salt thereof wherein
W is a structure i or ii; 
R1 is
(a) H,
(b) C1-8 alkyl, optionally substituted with one to three F, Cl, OH, OC(xe2x95x90O)C1-4 alkyl, or OC1-4 alkyl,
(c) C3-6 cycloalkyl,
(d) amino,
(e) C1-8 alkylamino,
(f) C1-8 dialkylamino, or
(g) OC1-8 alkyl;
R2 is H or F;
X is O or NR3;
R3 is
(a) H,
(b) C1-8 alkyl, optionally substituted with one to three F, Cl, OH, CN, NH2, OC(xe2x95x90O)C1-4 alkyl, or OC1-4 alkyl,
(c) C3-8 alkene, or
(d) C(xe2x95x90O)NR4R5;
R4 and R5 are independently
(a) H, or
(b) C1-8 alkyl, optionally substituted with one to three F, Cl, OH, CN, or NH2;
Y is O or S; and n is 0 or 1.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises an effective amount of the compound or salt),
a method of treating or preventing microbial infections in a mammal including skin and eye infections, comprising administering to said mammal in need of such treatment, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and
a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical treatment (e.g. the treatment or prevention of a microbial infection), and
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, xe2x80x9cEtxe2x80x9d for ethyl, xe2x80x9chxe2x80x9d for hour or hours and xe2x80x9crtxe2x80x9d for room temperature).
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-7alkyl refers to alkyl of one to seven carbon atoms, inclusive.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
The following definitions are used, unless otherwise described.
Alkyl denotes both straight and branched groups; but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to. Specifically, C1-8 alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, octyl and their isomeric forms thereof. Specifically, C1-4 alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, and their isomeric forms thereof.
Alkene denotes both straight and branched groups having at least one double bond. Specifically, C3-8 alkene can be allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and their isomeric forms thereof.
C3-6 cycloalkyl denotes a cycloalkyl having three to six carbon atoms. Specifically, C3-6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
Mammal denotes human and other warm blooded animals.
Pharmaceutically acceptable salts denotes those salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate, methanesulfonic acid salt and etc.
Compounds of the present invention may be in a form of pharmaceutically acceptable salts.
It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof.
A specific value for R1 is H.
A specific value for R1 is C1-8 alkyl, optionally substituted with one to three F, Cl, OH, OC(xe2x95x90O)C1-4 alkyl, or OC1-4 alkyl.
A specific value for R1 is C3-6 cycloalkyl.
A specific value for R1 is amino, C1-8 alkylamino, C1-8 dialkylamino.
A specific value for R1 is OC1-8 alkyl.
A preferred value for R1 is methyl.
A specific value for R2 is F.
A specific value for X is O.
A specific value for X is NR3; wherein R3 is H.
A specific value for X is NR3; wherein R3 is C1-8 alkyl, optionally substituted with one to three F, Cl, OH, CN, NH2, OC(xe2x95x90O)C1-4 alkyl, or OC1-4 alkyl.
A specific value for X is NR3; wherein R3 is C3-8 alkene.
A specific value for X is NR3; wherein R3 is C(xe2x95x90O)NR4R5; wherein R4 and R5 are independently H or C1-8 alkyl, optionally substituted with one to three F, Cl, OH, CN, or NH2;
A preferred value for X is O.
Another preferred value for X is NH.
Another preferred value for X is NCH3.
A specific value for Y is O.
A specific value for Y is S.
A specific value for n is 0 or 1.
A preferred value for n is 1.
A preferred structure is structure I-A 
Examples of the present invention includes:
a) N-[[(5S)-3-[3-fluoro-4-[tetrahydro-1,1-dioxido-2-(2-propenyl)-2H-1,2-thiazin-4-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
b) N-[[(5S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
c) N-[[(5S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide,
d) N-[[(5S)-3-[-fluoro-4-(tetrahydro-2-methyl-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide,
e) N-[[(5S)-3-[4-(2,2-dioxido-1,2-oxathian-5-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide,
f) N-[[(5S)-3-[4-(1,1-dioxido-4-isothiazolidinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide, or
g) N-[[(5S)-3-[3-fluoro-4-(tetrahydro-2-methyl-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
The following Schemes describe the preparation of compounds of the present invention. All of the starting materials are commercially available or prepared by procedures described in these schemes or by procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in the Schemes are as defined above or as in the claims.
The 6-membered ring sultams (n=1, X=NR3, R3 is the same as defined above) may be prepared as outlined in Scheme 1. Also see Morris et al., J. Org. Chem., 1991, 56, 3549. Addition of aryl acetic acid ester 2 to vinyl sulfonamide 3 in the presence of base gives adduct 4. Removal of the protecting groups from 4 with trifluoroacetic acid gives 5. Ring closure of 5 with sodium hydride affords 6 which in turn may be reduced with sodium borohydride-trifluoroacetic acid to give sultam 7. The nitrogen atom of the sultam ring may be protected with an allyl group to give 8 and the nitro group of 8 subsequently reduced with sodium borohydride-cuprous bromide: dimethyl sulfide complex to give amine 9.
Amine 9 can be protected as a CBZ derivative 10 which in turn can be reacted with amido epoxide 11 in the presence of base to give oxazolidinone 12. Removal of the N-allyl group can be effected with palladium on carbon in the presence of boron trifluoride etherate in ethanol to give 13. Replacement of H with R3 using methods known to those skilled in the art provides compound 14. Finally, thioamide 15 may be prepared by treating amide 14 with Lawesson""s Reagent.
The 6-membered ring sultones (n=1, X=O) may be prepared analogously to the sultams and the syntheses are outlined in Scheme II. Addition of methyl arylacetate 2 to vinyl sulfonate in the presence of base affords adduct 16. Reduction of the ester of 16 with DIBAL gives alcohol 17 which may be cyclized to sultone 18 in the presence of sodium hydride. A similar sequence of steps to those outlined for the sultam in Scheme I, converts 18 to the sultone oxazolidinones 19.
The preparation of 5-membered ring sultam is outlined in Scheme III. Alkylation of methyl arylacetate 2 with bromomethylsulfonamide 20 gives the adduct 21, which in the presence of base may be cyclized to 22. A similar sequence of steps as outlined in Scheme 1 converts 22 to sultam oxazolidinones 23. See DuPriest at al., J.Med Chem. 1991, 34, 3229 and Morris et al., J org. Chem., 1991, 56, 3549. 